Abnormal Epigenetic Modifications Research Articles

Phytocompounds targeting epigenetic modulations: an assessment in cancer.

For centuries, plants have been serving as sources of potential therapeutic agents. In recent years, there has been a growing interest in investigating the effects of plant-derived compounds on epigenetic processes, a novel and captivating Frontier in the field of epigenetics research. Epigenetic changes encompass modifications to DNA, histones, and microRNAs that can influence gene expression. Aberrant epigenetic changes can perturb key cellular processes, including cell cycle control, intercellular communication, DNA repair, inflammation, stress response, and apoptosis. Such disruptions can contribute to cancer development by altering the expression of genes involved in tumorigenesis. However, these modifications are reversible, offering a unique avenue for therapeutic intervention. Plant secondary compounds, including terpenes, phenolics, terpenoids, and sulfur-containing compounds are widely found in grains, vegetables, spices, fruits, and medicinal plants. Numerous plant-derived compounds have demonstrated the potential to target these abnormal epigenetic modifications, including apigenin (histone acetylation), berberine (DNA methylation), curcumin (histone acetylation and epi-miRs), genistein (histone acetylation and DNA methylation), lycopene (epi-miRs), quercetin (DNA methylation and epi-miRs), etc. This comprehensive review highlights these abnormal epigenetic alterations and discusses the promising efficacy of plant-derived compounds in mitigating these deleterious epigenetic signatures in human cancer. Furthermore, it addresses ongoing clinical investigations to evaluate the therapeutic potential of these phytocompounds in cancer treatment, along with their limitations and challenges.

Insights into the Roles of Epigenetic Modifications in Ferroptosis.

Ferroptosis is a non-apoptotic mode of cell death driven by membrane lipid peroxidation and is characterized by elevated intracellular levels of Fe2+, ROS, and lipid peroxidation. Studies have shown that ferroptosis is related to the development of multiple diseases, such as cancer, neurodegenerative diseases, and acute myeloid leukemia. Ferroptosis plays a dual role in the occurrence and development of these diseases. Ferroptosis mainly involves iron metabolism, ROS, and lipid metabolism. Various mechanisms, including epigenetic regulation, have been reported to be deeply involved in ferroptosis. Abnormal epigenetic modifications have been reported to promote tumor onset or other diseases and resistance to chemotherapy drugs. In recent years, diversified studies have shown that epigenetic modification is involved in ferroptosis. In this review, we reviewed the current resistance system of ferroptosis and the research progress of epigenetic modification, such as DNA methylation, RNA methylation, non-coding RNAs, and histone modification in cancer and other diseases by regulating ferroptosis.

Correlation of DNA methylation of DNMT3A and TET2 with oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy worldwide. Abnormal epigenetic modifications, including DNA methylation, are hallmarks of cancer and implicated in the development of various tumors. DNA methylation is catalyzed by the DNA methyltransferase and ten-eleven translocation dioxygenase families, with DNMT3A and TET2 being the most widely studied members, respectively. The correlation of methylation β values and clinical features was conducted in patients with OSCC in The Cancer Genome Atlas database. DNA methylation and protein expression levels of DNMT3A and TET2 in tissues were analyzed with methylation-specific polymerase chain reaction (MSP) and western blotting. To evaluate the effects of DNMT3A and TET2 on the biological characteristics of OSCC, cell proliferation was assessed with 5-ethynyl-2'-deoxyuridine, and cell migration capacity was quantified with wound healing and transwell assays. A survival analysis was performed with the Kaplan–Meier approach. The correlation between different methylation β values and clinical features was revealed. MSP revealed varying methylation degrees of DNMT3A and TET2 in OSCC tissues. Furthermore, western blotting showed that the protein expression levels were significantly different in cancer and surrounding healthy tissue samples. In vitro experiments demonstrated that DNMT3A knockdown and TET2 overexpression could inhibit the proliferation and migration of OSCC. Survival analysis revealed that patients with high DNMT3A methylation levels showed higher survival rates.

Analysis of histone H3K4me3 modifications in bovine placenta derived from different calf-production methods.

In ruminants, the overgrowth of offspring produced by invitro fertilization (IVF) is a common problem. Abnormal epigenetic modifications caused by environmental factors during the early embryonic period are suspected as an aetiology of overgrowth. In this study, we investigated the genome-wide histone H3K4me3 profiles of bovine placentae that play a pivotal role in foetal development and compared their characteristics between artificial insemination (AI)- and IVF-derived samples. Cotyledons were harvested from the placentae obtained at parturition of 5 AI- and 13 IVF-derived calves, and chromatin immunoprecipitation sequencing was performed for H3K4me3. We confirmed no significant maternal tissue contamination in the samples we used. The revealed H3K4me3 profiles reflected the general characteristics of the H3K4me3 modification, which is abundantly distributed in the promoter region of active genes. By extracting common modifications from multiple samples, the genes involved in placenta-specific biological processes could be enriched. Comparison with the H3K4me3 modifications of blastocyst samples was also effective for enriching the placenta-specific features. Principal component analysis suggested the presence of differential H3K4me3 modifications in AI- and IVF-derived samples. The genes contributing to the difference were related to the developmental biological processes. Imprinted genes such as BEGAIN, ZNF215 and DLX5 were among the extracted genes. Principal component and discriminant analyses using only male samples categorized the samples into three groups based on foetal weight and calf-production methods. To our knowledge, this is the first study to profile the genome-wide histone modifications of bovine foetal placentae and reveal their differential characteristics between different calf-production methods.

Lipid Metabolism, Methylation Aberrant, and Osteoporosis: A Multi-omics Study Based on Mendelian Randomization.

Observational studies have shown a causal association between dyslipidemia and osteoporosis, but the genetic causation and complete mechanism of which are uncertain. The disadvantage of previous observational studies is that they are susceptible to confounding factors and bias, that makes it difficult to infer a causal link between those two diseases. Abnormal epigenetic modifications, represented by DNA methylation, are important causes of many diseases. However, there are no studies showing a bridging role for methylation modifications in blood lipid metabolism and osteoporosis. SNPs for lipid profile (Blood VLDL cholesterol (VLDL-C), blood LDL cholesterol (LDL-C), blood HDL cholesterol (HDL-C), blood triglycerides (TG), diagnosed pure hypercholesterolaemia, blood apolipoprotein B (Apo B), blood apolipoprotein A1(Apo A1)), and bone mineral density (BMD) in different body parts (Heel BMD, lumbar BMD, whole-body BMD, femoral neck BMD) were obtained from large meta-analyses of genome-wide association studies as instrumental variables for two-sample Mendelian randomization. Assessment of the genetic effects of lipid profile-associated methylation sites and bone mineral density was carried out using the summary-data-based Mendelian randomization (SMR) method. Two-sample Mendelian randomization showed that there was a negative causal association between hypercholesterolaemia and heel BMD (p = 0.0103, OR = 0.4590), and total body BMD (p = 0.0002, OR = 0.2826). LDL-C had a negative causal association with heel BMD (p = 8.68E-05, OR = 0.9586). VLDL-C had a negative causal association with heel BMD (p = 0.035, OR = 0.9484), lumbar BMD (p = 0.0316, OR = 0.9356), and total body BMD (p = 0.0035, OR = 0.9484). HDL-C had a negative causal association with heel BMD (p = 1.25E-05, OR = 0.9548), lumbar BMD (p = 0.0129, OR = 0.9358), and total body BMD (p = 0.0399, OR = 0.9644). Apo B had a negative causal association with heel BMD (p = 0.0001, OR = 0.9647). Apo A1 had a negative causal association with heel BMD (p = 0.0132, OR = 0.9746) and lumbar BMD (p = 0.0058, OR = 0.9261). The p-values of all positive results corrected by the FDR method remained significant and sensitivity analysis showed that there was no horizontal pleiotropy in the results despite the heterogeneity in some results. SMR identified 3 methylation sites associated with lipid profiles in the presence of genetic effects on BMD: cg15707428(GREB1), cg16000331(SREBF2), cg14364472(NOTCH1). Our study provides insights into the potential causal links and co-pathogenesis between dyslipidemia and osteoporosis. The genetic effects of dyslipidaemia on osteoporosis may be related to certain aberrant methylation genetic modifications.

Intrauterine developmental origin, programming mechanism, and prevention strategy of fetal-originated hypercholesterolemia.

There is increasing evidence that hypercholesterolemia has an intrauterine developmental origin. However, the pathogenesis of fetal-originated is still lacking in a theoretical system, which makes its clinical early prevention and treatment difficult. It has been found that an adverse environment during pregnancy (e.g., xenobiotic exposure) may lead to changes in fetal blood cholesterol levels through changing maternal cholesterol metabolic function and/or placental cholesterol transport function and may also directly affect the liver cholesterol metabolic function of the offspring in utero and continue after birth. Adverse environmental conditions during pregnancy may also raise maternal glucocorticoid levels and promote the placental glucocorticoid barrier opening, leading to fetal overexposure to maternal glucocorticoids. Intrauterine high-glucocorticoid exposure can alter the liver cholesterol metabolism of offspring, resulting in an increased susceptibility to hypercholesterolemia after birth. Abnormal epigenetic modifications are involved in the intrauterine programming mechanism of fetal-originated hypercholesterolemia. Some interventions targeted at pregnant mothers or offspring in early life have been proposed to effectively prevent and treat the development of fetal-originated hypercholesterolemia. In this paper, the recent research progress on fetal-originated hypercholesterolemia was reviewed, with emphasis on intrauterine maternal glucocorticoid programming mechanisms, in order to provide a theoretical basis for its early clinical warning, prevention, and treatment.

Altered H3K4me3 profile at the TFAM promoter causes mitochondrial alterations in preadipocytes from first-degree relatives of type 2 diabetics

BackgroundFirst-degree relatives of type 2 diabetics (FDR) exhibit a high risk of developing type 2 diabetes (T2D) and feature subcutaneous adipocyte hypertrophy, independent of obesity. In FDR, adipose cell abnormalities contribute to early insulin-resistance and are determined by adipocyte precursor cells (APCs) early senescence and impaired recruitment into the adipogenic pathway. Epigenetic mechanisms signal adipocyte differentiation, leading us to hypothesize that abnormal epigenetic modifications cause adipocyte dysfunction and enhance T2D risk. To test this hypothesis, we examined the genome-wide histone profile in APCs from the subcutaneous adipose tissue of healthy FDR.ResultsSequencing-data analysis revealed 2644 regions differentially enriched in lysine 4 tri-methylated H3-histone (H3K4me3) in FDR compared to controls (CTRL) with significant enrichment in mitochondrial-related genes. These included TFAM, which regulates mitochondrial DNA (mtDNA) content and stability. In FDR APCs, a significant reduction in H3K4me3 abundance at the TFAM promoter was accompanied by a reduction in TFAM mRNA and protein levels. FDR APCs also exhibited reduced mtDNA content and mitochondrial-genome transcription. In parallel, FDR APCs exhibited impaired differentiation and TFAM induction during adipogenesis. In CTRL APCs, TFAM-siRNA reduced mtDNA content, mitochondrial transcription and adipocyte differentiation in parallel with upregulation of the CDKN1A and ZMAT3 senescence genes. Furthermore, TFAM-siRNA significantly expanded hydrogen peroxide (H2O2)-induced senescence, while H2O2 did not affect TFAM expression.ConclusionsHistone modifications regulate APCs ability to differentiate in mature cells, at least in part by modulating TFAM expression and affecting mitochondrial function. Reduced H3K4me3 enrichment at the TFAM promoter renders human APCs senescent and dysfunctional, increasing T2D risk.Graphical abstract

Epigenetic modification in diabetic kidney disease.

Diabetic kidney disease (DKD) is a common microangiopathy in diabetic patients and the main cause of death in diabetic patients. The main manifestations of DKD are proteinuria and decreased renal filtration capacity. The glomerular filtration rate and urinary albumin level are two of the most important hallmarks of the progression of DKD. The classical treatment of DKD is controlling blood glucose and blood pressure. However, the commonly used clinical therapeutic strategies and the existing biomarkers only partially slow the progression of DKD and roughly predict disease progression. Therefore, novel therapeutic methods, targets and biomarkers are urgently needed to meet clinical requirements. In recent years, increasing attention has been given to the role of epigenetic modification in the pathogenesis of DKD. Epigenetic variation mainly includes DNA methylation, histone modification and changes in the noncoding RNA expression profile, which are deeply involved in DKD-related inflammation, oxidative stress, hemodynamics, and the activation of abnormal signaling pathways. Since DKD is reversible at certain disease stages, it is valuable to identify abnormal epigenetic modifications as early diagnosis and treatment targets to prevent the progression of end-stage renal disease (ESRD). Because the current understanding of the epigenetic mechanism of DKD is not comprehensive, the purpose of this review is to summarize the role of epigenetic modification in the occurrence and development of DKD and evaluate the value of epigenetic therapies in DKD.

Epigenetic inhibitors and their role in cancer therapy.

Epigenetic modifications to DNA are crucial for normal cellular and biological functioning. DNA methylation, histone modifications, and chromatin remodeling are the most common epigenetic mechanisms. These changes are heritable but still reversible. The aberrant epigenetic alterations, such as DNA methylation, histone modification, and non-coding RNA (ncRNA)-mediated gene regulation, play an essential role in developing various human diseases, including cancer. Recent studies show that synthetic and dietary epigenetic inhibitors attenuate the abnormal epigenetic modifications in cancer cells and therefore have strong potential for cancer treatment. In this chapter, we have highlighted various types of epigenetic modifications, their mechanism, and as drug targets for epigenetic therapy.

Acetyl-CoA: An interplay between metabolism and epigenetics in cancer

Due to its high mortality and severe economic burden, cancer has become one of the most difficult medical problems to solve today. As a key node in metabolism and the main producer of energy, acetyl-coenzyme A (acetyl-CoA) plays an important role in the invasion and migration of cancer. In this review, we discuss metabolic pathways involving acetyl-CoA, the targeted therapy of cancer through acetyl-CoA metabolic pathways and the roles of epigenetic modifications in cancer. In particular, we emphasize that the metabolic pathway of acetyl-CoA exerts a great impact in cancer; this process is very different from normal cells due to the “Warburg effect”. The concentration of acetyl-CoA is increased in the mitochondria of cancer cells to provide ATP for survival, hindering the growth of normal cells. Therefore, it may be possible to explore new feasible and more effective treatments through the acetyl-CoA metabolic pathway. In addition, a growing number of studies have shown that abnormal epigenetic modifications have been shown to play contributing roles in cancer formation and development. In most cancers, acetyl-CoA mediated acetylation promotes the growth of cancer cells. Thus, acetylation biomarkers can also be detected and serve as potential cancer prediction and prognostic markers.

An integrated multi-omics analysis of topoisomerase family in pan-cancer: Friend or foe?

BackgroundTopoisomerases are nuclear enzymes that get to the bottom of topological troubles related with DNA all through a range of genetic procedures. More and more studies have shown that topoisomerase-mediated DNA cleavage plays crucial roles in tumor cell death and carcinogenesis. There is however still a lack of comprehensive multi-omics studies related to topoisomerase family genes from a pan-cancer perspective.MethodsIn this study, a multiomics pan-cancer analysis of topoisomerase family genes was conducted by integrating over 10,000 multi-dimensional cancer genomic data across 33 cancer types from The Cancer Genome Atlas (TCGA), 481 small molecule drug response data from cancer therapeutics response portal (CTRP) as well as normal tissue data from Genotype-Tissue Expression (GTEx). Finally, overall activity-level analyses of topoisomerase in pan-cancers were performed by gene set variation analysis (GSVA), together with differential expression, clinical relevancy, immune cell infiltration and regulation of cancer-related pathways.ResultsDysregulated gene expression of topoisomerase family were related to genomic changes and abnormal epigenetic modifications. The expression levels of topoisomerase family genes could significantly impact cancer progression, intratumoral heterogeneity, alterations in the immunological condition and regulation of the cancer marker-related pathways, which in turn caused the differences in potential drugs sensitivity and the distinct prognosis of patients.ConclusionIt was anticipated that topoisomerase family genes would become novel prognostic biomarkers for cancer patients and provide new insights for the diagnosis and treatment of tumors.

Histone modification and histone modification-targeted anti-cancer drugs in breast cancer: Fundamentals and beyond.

Dysregulated epigenetic enzymes and resultant abnormal epigenetic modifications (EMs) have been suggested to be closely related to tumor occurrence and progression. Histone modifications (HMs) can assist in maintaining genome stability, DNA repair, transcription, and chromatin modulation within breast cancer (BC) cells. In addition, HMs are reversible, dynamic processes involving the associations of different enzymes with molecular compounds. Abnormal HMs (e.g. histone methylation and histone acetylation) have been identified to be tightly related to BC occurrence and development, even though their underlying mechanisms remain largely unclear. EMs are reversible, and as a result, epigenetic enzymes have aroused wide attention as anti-tumor therapeutic targets. At present, treatments to restore aberrant EMs within BC cells have entered preclinical or clinical trials. In addition, no existing studies have comprehensively analyzed aberrant HMs within BC cells; in addition, HM-targeting BC treatments remain to be further investigated. Histone and non-histone protein methylation is becoming an attractive anti-tumor epigenetic therapeutic target; such methylation-related enzyme inhibitors are under development at present. Consequently, the present work focuses on summarizing relevant studies on HMs related to BC and the possible mechanisms associated with abnormal HMs. Additionally, we also aim to analyze existing therapeutic agents together with those drugs approved and tested through pre-clinical and clinical trials, to assess their roles in HMs. Moreover, epi-drugs that target HMT inhibitors and HDAC inhibitors should be tested in preclinical and clinical studies for the treatment of BC. Epi-drugs that target histone methylation (HMT inhibitors) and histone acetylation (HDAC inhibitors) have now entered clinical trials or are approved by the US Food and Drug Administration (FDA). Therefore, the review covers the difficulties in applying HM-targeting treatments in clinics and proposes feasible approaches for overcoming such difficulties and promoting their use in treating BC cases.

The role of RNA modification in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly mortal type of primary liver cancer. Abnormal epigenetic modifications are present in HCC, and RNA modification is dynamic and reversible and is a key post-transcriptional regulator. With the in-depth study of post-transcriptional modifications, RNA modifications are aberrantly expressed in human cancers. Moreover, the regulators of RNA modifications can be used as potential targets for cancer therapy. In RNA modifications, N6-methyladenosine (m6A), N7-methylguanosine (m7G), and 5-methylcytosine (m5C) and their regulators have important regulatory roles in HCC progression and represent potential novel biomarkers for the confirmation of diagnosis and treatment of HCC. This review focuses on RNA modifications in HCC and the roles and mechanisms of m6A, m7G, m5C, N1-methyladenosine (m1A), N3-methylcytosine (m3C), and pseudouridine (ψ) on its development and maintenance. The potential therapeutic strategies of RNA modifications are elaborated for HCC.

Magnetic multi-enzyme cascade combined with liquid chromatography tandem mass spectrometry for fast DNA digestion and quantitative analysis of 5-hydroxymethylcytosine in genome of human bladder cancer T24 cells induced by tetrachlorobenzoquinone

Long-term exposure to halobenzoquinones (HBQs) can induce genomic damages and abnormal epigenetic modifications. High-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) has shown unique advantages in identification and sensitive analysis of these structurally modified DNA lesions. Prior to MS analysis, genomic DNA needs to be fully digested into mono-nucleosides. Here, we prepared Supernuclease (SN)-, snake venom phosphodiesterase (SVP)- and calf intestinal alkaline phosphatase (CIP)- individually immobilized magnetic nanoparticles (MNPs), and combined them according to certain formula to construct a recyclable SN-SVP-CIP magnetic nanoparticles (SNSC-MNPs) cascade for rapid and efficient DNA digestion. The SNSC-MNPs cascade can fully digest genomic DNA into mono-nucleosides within 30 min. The SNSC-MNPs cascade coupled with HPLC-MS/MS method can accurately and sensitively detect 5-hydroxymethylcytosine (5hmC) changes in genome of human bladder cancer T24 cells induced by tetrachlorobenzoquinone. The immobilization of enzymes on MNPs can enhance the stability and enzymatic activity of the three enzymes, which guarantees the reusability and longtime preservation of the cascades. The relative digestive efficiencies are among 86% -106% up to ten times of reuse. The newly synthesized SNSC-MNPs cascade coupled with HPLC-MS/MS method is promising for fast identification and analysis of structural modifications in genomic DNA.

Multi-omics analysis reveals the panoramic picture of necroptosis-related regulators in pan-cancer.

Background: Unlike apoptosis, necroptosis is a tightly regulated form of programmed cell death (PCD) that occurs in a caspase-independent manner and is mainly triggered by receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 and the RIPK3 substrate mixed-lineage kinase domain-like protein (MLKL). A growing body of evidence has documented that necroptosis, as a novel therapeutic strategy to overcome apoptosis resistance, has potential pro- or anti-tumoral effects in tumorigenesis, metastasis, and immunosurveillance. However, comprehensive multi-omics studies on regulators of necroptosis from a pan-cancer perspective are lacking.Methods: In the present study, a pan-cancer multi-omics analysis of necroptosis-related regulators was performed by integrating over 10,000 multi-dimensional cancer genomic data across 33 cancer types from TCGA, 481 small-molecule drug response data from CTRP, and normal tissue data from GTEx. Pan-cancer pathway-level analyses of necroptosis were conducted by gene set variation analysis (GSVA), including differential expression, clinical relevance, immune cell infiltration, and regulation of cancer-related pathways.Results: Genomic alterations and abnormal epigenetic modifications were associated with dysregulated gene expression levels of necroptosis-related regulators. Changes in the gene expression levels of necroptosis-related regulators significantly influenced cancer progression, intratumoral heterogeneity, alterations in the immunological condition, and regulation of cancer marker-related pathways. These changes, in turn, caused differences in potential drug sensitivity and the prognosis of patients.Conclusion: Necroptosis-related regulators are expected to become novel biomarkers of prognosis and provide a fresh perspective on cancer diagnosis and treatment.

Non-invasive chromosome screening for embryo preimplantation using cell-free DNA

Abstract Preimplantation genetic testing (PGT) is a widely adopted screening method that can be performed to identify and select embryos with normal ploidy; however, PGT relies on embryo biopsy, that is, polar body, embryo cells, or trophectoderm biopsy, to obtain embryonic DNA, increase its technical limitations. Studies have indicated that biopsy may have an influence on the quality and development of embryos, and increase the chance of abnormal epigenetic modifications. Therefore, non-invasive PGT (niPGT) detection of cell-free DNA (cfDNA) has gradually become a hot research topic in the field of assisted reproduction. Studies showed cfDNA could be detected in blastocyst fluid and spent culture medium (SCM) in vitro cultured embryos. The cfDNA collection requires less skill and makes lower risk to embryos. Some studies have been conducted to evaluate the feasibility of SCM-based niPGT approaches. When comparing the ploidy consistency of cfDNA in SCM, its consistency to the conventional PGT for aneuploidies results fluctuated widely, it is critical to recognize the factors influencing accuracy. These contradictory results may be related to factors such as the difference in SCM sampling methods and sampling time, and the definition of consistency. In this review, we aimed to comprehensively summarize how researchers use embryonic cfDNA to conduct niPGT detection. It also systematically reviews the factors affecting the accuracy of the test and its underlying issues, as well as prospective applications. We hope to provide a basis for future niPGT research and a useful reference for the standardized operation of niPGT that can be widely applied in clinical practice.

Effect of ACY-1215 on cytoskeletal remodeling and histone acetylation in bovine somatic cell nuclear transfer embryos

The latest studies indicated that in addition to alterations in abnormal chromosome epigenetic modifications, the abnormal cytoskeletal changes are also an important cause for the developmental failure of somatic cell nuclear transfer (SCNT) embryos. In the present study, the effects of ACY-1215, a specific inhibitor of HDAC6, on the acetylation of α-tubulin, histone epigenetic modification, spindle formation and embryonic development of early bovine SCNT embryos were studied. The results showed that acetylation of α-tubulin, H3K9, and H4K16 was significantly lower in SCNT embryos than in vitro fertilization (IVF) embryos. After ACY-1215 treatment, the acetylation level of α-tubulin, H3K9, and H4K16 of SCNT embryos was closer to that of IVF embryos. ACY-1215 treatment reduced spindle abnormalities, delayed the time of first cleavage of embryos, increased the total cell number and trophectoderm cells numbers, and reduced apoptosis in SCNT blastocysts. ACY-1215 regulated the process of embryonic epigenetic modification and cytoskeletal protein acetylation, corrected abnormal development of SCNT embryos, and improved SCNT embryonic development potential.

Optical Imaging of Epigenetic Modifications in Cancer: A Systematic Review.

Increasing evidence has demonstrated that abnormal epigenetic modifications are strongly related to cancer initiation. Thus, sensitive and specific detection of epigenetic modifications could markedly improve biological investigations and cancer precision medicine. A rapid development of molecular imaging approaches for the diagnosis and prognosis of cancer has been observed during the past few years. Various biomarkers unique to epigenetic modifications and targeted imaging probes have been characterized and used to discriminate cancer from healthy tissues, as well as evaluate therapeutic responses. In this study, we summarize the latest studies associated with optical molecular imaging of epigenetic modification targets, such as those involving DNA methylation, histone modification, noncoding RNA regulation, and chromosome remodeling, and further review their clinical application on cancer diagnosis and treatment. Lastly, we further propose the future directions for precision imaging of epigenetic modification in cancer. Supported by promising clinical and preclinical studies associated with optical molecular imaging technology and epigenetic drugs, the central role of epigenetics in cancer should be increasingly recognized and accepted.

Insufficient pyruvate in culture medium arrests mouse embryos at the first cleavage stage associated with abnormal epigenetic modifications

Energy is essential for early embryogenesis, and fertilized eggs can successfully develop to blastocyst in in vitro culture medium with an appropriate energy supply. Conversely, embryonic development is negatively affected by a suboptimal energy supply. We previously observed that a low level of pyruvate greatly arrests mouse embryos at the 2-cell stage. However, how methylation modifications are affected at this specific stage remains unknown. In this study, we found that mouse embryos could timely develop to the 4-cell stage in K+simplex optimized medium (KSOM) with control level of pyruvate, but embryos were significantly arrested at the 2-cell stage when pyruvate was reduced to 0.2-fold of the control level. Moreover, the fluorescence intensities of 5 mC, H3K4me2, H3K9me2 and H3K27me2 in the 2-cell stage embryos of the 0.2-fold pyruvate group were notedly lower than those of the control group, but N6-methyladenosine (m6A) fluorescence intensity was higher, suggesting that global genomic DNA, histone and m6A methylation modifications are disrupted with low levels of pyruvate. Consistently, the mRNA levels of genes related to DNA methylation, histone methylation and m6A modifications were also disturbed in the 2-cell stage embryos cultured with low levels of pyruvate. In summary, our findings demonstrate that insufficient pyruvate in culture medium results in mouse embryonic developmental arrest, at least in part due to defects in methylation modifications.

Emerging Insights Into the Role of Epigenetics and Gut Microbiome in the Pathogenesis of Graves' Ophthalmopathy.

Graves’ Ophthalmopathy (GO) is an organ-specific autoimmune disease that is often characterized by infiltration of orbital tissues and is considered as the most common extra-thyroid manifestation of Graves’ disease (GD). Although genetic susceptibility has been found to be critical for the phenotype of GO, the associated risk alleles in a single gene are generally insufficient to cause the disease. Accruing evidence has shown that epigenetic disorders can act as the potentially missing link between genetic risk and clinically significant disease development. Abnormal epigenetic modifications can lead to pro-inflammatory cascades and activation of orbital fibroblasts (OFs) by promoting the various inflammatory response pathways and regulating the diverse signaling molecules that are involved in the fibrogenesis and adipogenesis, thereby leading to the significant expansion of orbital tissues, fibrosis and inflammation infiltration. Additionally, emerging evidence has shown that the gut microbiome can possibly drive the pathogenesis of GO by influencing the secretion of Thyrotropin receptor antibody (TRAb) and T-helper 17 (Th17)/regulatory T cells (Treg) imbalance. This paper describes the latest epigenetic research evidence and progress made in comprehending the mechanisms of GO development, such as DNA methylation, histone modification, non-coding RNAs, and the gut microbiome.